Delayed Release Tablet with Defined Core Geometry

ABSTRACT

A tablet comprising a core containing an active agent, and a coating, the core being disposed within the coating such that the coating has a thickness about a longitudinal axis (X-Y) of about 4.85 to 4.95 mm. The position of the core within the coating dictating that the active agent is released rapidly after a lag time during which time no active agent is released.

This invention is concerned with a tablet comprising a core containing adrug substance and a coating that is applied to said core by means ofcompression-coating techniques. The tablet can contain all manner ofdrug substances, but is particularly suitable for administering thosethat are advantageously released only after a predetermined lag timeafter administration. The tablets are particularly suitable foradministering lucocorticosteroids selected from prednisone, prednisoloneor methylprednisolone.

Research into the chronopharmacological field has demonstrated theimportance of biological rhythms in drug therapy. Very often, optimalclinical outcomes cannot be achieved if a drug is released constantlyafter ingestion. This is particularly the case if symptoms of a diseasedisplay circadian variations. In such cases, drug release should vary ina manner that is sympathetic to these variations in order that drugplasma concentrations are at an optimal therapeutic level only whenrequired to treat symptoms of a disease state.

In particular, if symptoms of a disease become apparent at night, or inthe early hours upon waking, the time when a patient must take itsmedication in order to affect the best clinical outcome requiresdetailed consideration. For example, most asthma attacks occur in theearly hours of the morning, e.g. 4 am to 6 am. This is a result ofcomplex circadian rhythms such as the secretion of hydrocortisone andadrenaline. Ischaemic heart diseases occur most often during the nightor in the early waking hours around breakfast time. Stiffness and painassociated with rheumatoid arthritis and osteoarthritis occur in theearly waking hours, which is believed to be as a result of the secretionof IL-6 in the early hours of the morning, e.g. around 2 am to 4 am.

With conventional immediate release dosage forms, synchronization ofdrug administration with a nocturnal circadian rhythm responsible forthe symptoms experienced by a patient would require a patient having tobe disturbed from sleep to take a medicament during the early hours ofthe morning in order to achieve the most efficacious clinical outcome.Of course, this would be highly inconvenient for a patient.

Accordingly, there remains a need to provide dosage forms that can betaken at a convenient hour before bedtime that will release an effectivedose of a drug substance only after a pre-determined lag time in orderto synchronise peak plasma concentrations of drug with a particularcircadian rhythm.

Furthermore, particularly in relation to drug substances that have anarrow absorption window, or in the case of drug substances that areadapted to treat a local condition in the colon such as Crohn's disease,ulcerative colitis, IBS and IBD there is also a need to provide a dosageform that rapidly releases the drug substances after reaching the end ofthe lag time.

Still further, having regard to the varied life styles of patients, inorder to reduce the inter- and intra-subject variance in bioavailabilitythere is a need to provide a dosage form that releases a drug with areliable lag time, and to provide peak plasma drug concentrations at apre-determined time, irrespective of whether a patient is in a fed orfasted state.

Time controlled release formulations are known in the art that are ableto deliver drug substances with a defined release rate after a lag timeduring which no drug substance is released. Such a dosage form isdisclosed in WO 02/072033. This dosage form is characterized by acoating containing a natural or synthetic gum that gels in the presenceof aqueous media. The coating acts as a bather to the ingress of aqueousmedia into an active-agent-containing core and thereby creating a lagtime during which no drug substance is released. The gellable coatingacts as a medium through which drug is released in a delayed or modifiedmanner. It is stated that the lag time can be modulated by varying thecoating weight.

There are several problems with such an approach: First, release of thedrug occurs by means of diffusion through the gelled coating. In thecase of drugs that have a narrow absorption window, or in the case ofdrugs adapted to treat a relatively small affected area of the GI tractor colon, once the lag time has expired it is desirable to release thedrug as rapidly as possible to ensure that all or substantially all ofthe drug released at the desired site. A slow diffusion of the drug isnot appropriate in such cases. Further, by attempting to control lagtime by controlling the coating weight, the formulator's latitude islimited in this regard, because increasing coating weight addsadditional cost to the dosage form, and it also adds to the size of thedosage form, which may make it difficult to swallow for certain patientpopulations such as minors and for the elderly or infirm. Still further,merely adjusting coat weight does not ensure that a coating is of adesired thickness at a particular site. It remains that if the core isnot correctly positioned within a die of a press coating machine,despite having selected a particular coat weight, part of the coatingmay be unintentionally thinner than desired, resulting in unforeseenpremature release of the drug.

The applicant has now surprisingly found that by carefully selecting thegeometry of a core within its coating, it is possible to manipulate thecoating thickness at specific points on the tablet to ensure anappropriate coating thickness to produce tablets having a specificallytuned lag time. Furthermore, because one is able to increase thicknesswhere it is needed in the coating, one can reduce coating material toallow use of the minimum amount necessary to achieve the desired releasecharacteristics, thus saving on cost of materials and also reducing theoverall tablet size.

Still further, the applicant has found that by selecting appropriatecore and coating materials, one is able not only to accurately controlthe lag time, one is also to ensure that all, or substantially all, ofthe drug substance upon expiry of the lag time is released rapidly andat the absorption site, or the locally affected site.

Accordingly, in a first aspect of the present invention there isprovided a tablet comprising a core containing an drug substance, and acoating around said core, the core being disposed within said coatingsuch that the coating thickness about an axis (X-Y) (see FIG. 1) isthicker than the coating about an axis (A-B) (see FIG. 1) orthogonal to(X-Y), and wherein the thickness of the coating about the axis (X-Y) isselected such that the coating is adapted to rupture upon immersion inan aqueous medium after a period of between about 2 to 6 hours.

According to the present invention, the coating thickness about the axis(X-Y) is thicker than the coating about the axis (A-B). The ratio of thethickness of the coating about the axis (X-Y) to the thickness of thecoating about the axis (A-B) may be from 2.2 to 2.6:1.0 to 1.6.

In another aspect of the invention there is provided a tablet comprisinga core containing an drug substance and a coating around said core, thecore being disposed within said coating such that the coating thicknessabout an axis (X-Y) is thicker than the coating about an axis (A-B)orthogonal to (X-Y), and the thickness of the coating about the axis(X-Y) is at least about 2.2 mm, particularly about 2.2 to 2.6 mm, moreparticularly about 2.35 to 2.45 mm.

The thickness of the coating around or about the axis (A-B) is notcritical for controlling the lag time. Accordingly, the formulator hassome latitude in selecting its thickness. It should not be so thick asto render the final tablet to large, yet on the other hand the coatingshould not be so thin that the coating is render weak and liable tocrack under the slightest mechanical stress. Preferably, the thicknessof the coating about the axis (A-B) is about 1.0 to about 1.6 mm. Thecoating thickness either side of the core on the axis (A-B) may or maynot be equal. For example, on a first side of the core (A-core) thecoating may have a thickness of about 1.2 to 1.6 mm, more preferably1.35 to 1.45 mm, whereas on the other side of the core (B-core) thethickness may be about 1.0 to 1.4 mm, more preferably 1.15 to 1.25 mm.

Accordingly, in a particular embodiment of the present invention thereis provided a tablet comprising a core containing an drug substance, anda coating, the core being disposed within the coating such that thecoating has a thickness about an axis (X-Y) of at least about 2.2 mm,more particularly about 2.2 to about 2.6 mm, still more particularly2.35 to 2.45 mm, and the thickness of the coating about an axis (A-B)orthogonal to (X-Y) is between 1.0 and 1.6 mm. More particularly, alongthe axis (A-B) on a first side of the core (A-core) the thickness may beabout 1.2 to 1.6 mm, more preferably 1.35 to 1.45 mm, and on a secondside of the core (B-core) the thickness may be about 1.0 to 1.4 mm, morepreferably 1.15 to 1.25 mm.

Tablets of the present invention are formed by compression coatingmethods as will be described in more detail herein below. Compressioncoated tablets are generally formed by placing a portion of a powderedcoating material in a die and tamping the powder into a compact formusing a punch. A core is then deposited onto the compacted coatingmaterial before the remainder of the coating material is introduced intothe die and compression forces are applied to form the coated tablet. Toensure that the core is placed on the tamped coating material to ensureits correct geometry relative to the coating in the final tablet form,it is preferable to employ means for positioning the core in relation tothe coating material in a die. Typically such means may be provided by apin punch. A pin punch is a punch that has a convex surface thatcontacts the coating material to leave a small depression or hollow inthe tamped coating material. Thus, when the core is placed into the dieon the tamped material, it sits in the depression or hollow and itscorrect geometry is assured in the final tablet form.

The thickness of the coating along and about the axis of the directionof movement of the punch (the “(A-B)” axis referred to above) isdetermined by the amount of coating material added to the die and thecompaction force applied to form the tablet. On the other hand, thethickness of the coating along and about the “(X-Y)” axis is determinedby the size of the core, its position within the die and the diameter ofthe die. It will be apparent to the skilled person that there is aplurality of axes (X-Y) orthogonal to the axis of movement of the punch(the “A-B” axis), which extend radially from the centre of the tablet toits circumference, and when the reference is made to the thickness ofthe coating about an axis X-Y, reference is being made the thicknessabout any or all of these axes.

During the compression of the coating around the core, the coatingmaterial above and below the core (the material along and about the(A-B) axis) is relatively highly compacted and dense. On the other hand,the coating material disposed along and about the (X-Y) axis issubjected to lower compaction forces and is relatively less dense.Accordingly, the material about the (X-Y) axis is relatively porous andpermissive towards the ingress of aqueous media. The rate of ingress ofthe aqueous medium through the coating along the direction of the X-Yaxis is, in part, responsible for controlling the release of the drugsubstance from the core. Once the aqueous medium contacts the core, thecore reacts by swelling or effervescing thereby to break open the coregenerally along the direction of ingress of the aqueous media (i.e. theX-Y axis) to form to essentially two hemispheres of coating materialthat may remain conjoined, which has an appearance of an opened clamshell. The reaction of the core material to the presence of the aqueousmedium is likewise in part responsible for controlling the release ofdrug substance from the core.

The hardness of the tablet is preferably at least 60 Newtons, e.g. 60 to80 Newtons, and more particularly 60 to 75 Newtons. Hardness may bemeasured according to a process described in The European Pharmacopoeia4, 2.9.8 at page 201. The test employs apparatus consisting of 2opposing jaws, one of which moves towards the other. The flat surfacesof the jaws are perpendicular to the direction of movement. The crushingsurfaces of the jaws are flat and larger than the zone of contact withthe tablet. The apparatus is calibrated using a system with a precisionof one Newton. The tablet is placed between the jaws. For eachmeasurement, the tablet is oriented in the same way with respect to thedirection of the applied force. Measurements are carried out on 10tablets. Results are expressed in terms of the mean, minimum and maximumvalues (in Newtons) of the force needed to crush the tablets.

Tablets having a hardness within this range are mechanically robust towithstand forces generated in the stomach, particularly in the presenceof food. Furthermore, the tablets are sufficiently porous about the(X-Y) plane of the tablet to permit ingress of physiological media tothe core at an appropriate rate to ensure that the drug substance isreleased within an appropriate lag time, e.g. within 2 to 6 hours.

As stated above, it is a preferred aspect of the present invention thatthe tablets are adapted to release a drug substance from the core aftera pre-determined lag time, as well as being adapted to release all, orsubstantially all, of the drug substance within a very short period oftime after the expiry of the lag time. This ensures that all, orsubstantially all, of the drug is released at the intended absorptionsite along the GI tract, or onto the affected site of the GI tract ifthe condition to be treated is a local topical condition. It ispreferred that the tablets of the present invention release all, orsubstantially all of a drug substance within about ½ hour to about 1hour after the selected lag time.

This aspect of the present invention is important for delivering drugshaving a rather narrow absorption window in the upper GI tract, such asthe glucocorticosteroids referred to above. In such cases, the drugshould be released before the tablet can pass into the bowel, whereabsorption of such drugs is poor. It is made particularly important ifthe tablet is intended to perform in the same manner independent of theeffects of food. It is well known that the rate at which a tablet willpass through the GI tract will vary depending on whether a patient is ina fed or fasted state. In the fasted state, a tablet will typicallyclear the stomach within about ½ hour and 1 hour after ingestion, andthereafter take a further 4 to 5 hours to clear the upper GI tractthrough the ileosecal junction. In a fed state, a tablet may take aslong as 4 hours to be cleared from the stomach, and a further 4 to 5hours to clear the upper GI tract. Accordingly, if a tablet is torelease of all, or substantially all, of its drug into the upper GItract irrespective of the fed state of a patient, it is preferable thatthe release the drug after the lag time occurs within a time limitreferred to in the paragraph above.

It should be understood that whereas it is desirable that no drugsubstance is released during the lag time, some release may occur.However, any release of drug substance during the lag time should notexceed 10% of the total amount of drug substance in the core.

The coating employed in a tablet according to the present invention ispreferably formed of insoluble or poorly water soluble hydrophobicmaterial. In use, the coating optimally acts merely as a barrier to theingress of aqueous physiological media thereby providing a drug releaselag time. For the reasons set forth above, optimally the tablet shouldhave the minimum thickness possible consistent with the desired lagtime. Accordingly, employing water insoluble or poorly, solublehydrophobic coating materials, one is able to produce a coating that isrelative recalcitrant to the ingress of moisture and so long lag timescan be achieved with relatively thin coatings.

Further, in order to achieve the rapid release of drug substance afterthe lag time has expired, it is desirable that the coating contains no,or substantially no, ingredients that swell and gel agents to such anextent that the coating acts as a diffusion barrier to the release ofdrug substance. In this regard, it is preferable that the coatingcontains no, or substantially no, materials such as natural or syntheticgums that modulate release of the drug substance through an intactswollen coating. Drug substance is released from the core as a result ofthe physical rupturing of the coating and not as a result of the drugsubstance diffusing through a swollen coating material. That themechanism of drug release is substantially dependent on the physicalsplitting of the coating, and not on a diffusion process through aswellable and gellable coating, means that a wide range of drugsubstances can be delivered from tablets according to the invention in areliable and reproducible manner.

The tablet coating may contain one or more water insoluble or poorlysoluble hydrophobic excipients. Such excipients may be selected from anyof the known hydrophobic cellulosic derivatives and polymers includingalkylcellulose, e.g. ethylcellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, and derivativesthereof; polymethacrylic polymers, polyvinyl acetate and celluloseacetate polymers; fatty acids or their esters or salts; long chain fattyalcohols; polyoxyethylene alkyl ethers; polyoxyethylene stearates; sugaresters; lauroyl macrogol-32 glyceryl, stearoyl macrogol-32 glyceryl, andthe like. Hydroxypropylmethyl cellulose materials are preferablyselected from those low Mw and low viscosity materials such as E-Typemethocel, and 29-10 types as defined in the USP.

Other agents or excipients that provide hydrophobic quality to coatingsmay be selected from any waxy substance known for use as tabletexcipients. Preferably they have a HLB value of less than 5, and morepreferably about 2. Suitable hydrophobic agents include waxy substancessuch as carnauba wax, paraffin, microcrystalline wax, beeswax, cetylester wax and the like; or non-fatty hydrophobic substances such ascalcium phosphate salts, e.g. dibasic calcium phosphate.

Preferably the coating contains a calcium phosphate salt, glycerylbehenate, and polyvinyl pyrollidone, or mixtures thereof, and one ormore adjuvants, diluents, lubricants or fillers.

Preferred components in the coating are as follows, with generallysuitable percentage amounts expressed as percentage weight of thecoating.

Polyvinyl pyrollidone (Povidone) is preferably present in amounts ofabout 1 to 25% by weight or the coating, more particularly 4 to 12%,e.g. 6 to 8%.

Glyceryl behenate is an ester of glycerol and behenic acid (a C22 fattyacid). Glyceryl behenate may be present as its mono-, di-, or tri-esterform, or a mixture thereof. Preferably it has an HLB value of less than5, more preferably approximately 2. It may be present in amounts ofabout 5 to 85% by weight of the coating, more particularly from 10 to70% by weight, and in certain preferred embodiments from 30 to 50%.

Calcium phosphate salt may be the dibasic calcium phosphate dihydrateand may be present in an amount of about 10 to 90% by weight of thecoating, preferably 20 to 80%, e.g. 40 to 75%.

The coating may contain other common tablet excipients such aslubricants, colourants, binders, diluents, glidants and taste-maskingagents or flavourants.

Examples of excipients include colourants such a ferric oxide, e.g.yellow ferric oxide; lubricants such as magnesium stearate; and glidantssuch as silicon dioxide, e.g. colloidal silicon dioxide. Yellow ferricoxide may be used in amounts of about 0.01 to 0.5% by weight based onthe coating; magnesium stearate may be present in amounts of 1 to 20% byweight of the coating, more preferably 2 to 10%, e.g. 0.5 to 1.0%; andcolloidal silica may be used in amounts of 0.1 to 20% by weight of thecoating, preferably 1 to 10%, more preferably 0.25 to 1.0%.

The core comprises in addition to a drug substance, a disintegratingagent or mixtures of disintegrating agents used in immediate releaseformulations and well know to persons skilled in the art. Thedisintegrating agents useful in the exercise of the present inventionmay be materials that effervesce and or swell in the presence of aqueousmedia thereby to provide a force necessary to mechanically disrupt thecoating material.

Preferably a core contains, in addition to the drug substance,cross-linked polyvinyl pyrollidone and croscarmellose sodium.

The following is a list of preferred core materials. The amounts areexpressed in terms of percentage by weight based on the weight of thecore.

Cross-linked polyvinyl pyrollidone is described above and is useful as adisintegrating agent, and may be employed in the core in the amountsdisclosed in relation to the core.

Croscamellose sodium is an internally cross-linked sodium carboxymethylcellulose (also known as Ac-Di-Sol) useful as a disintegrating agent.

Disintegrating agents may be used in amounts of 5 to 30% by weight basedon the core. However, higher amounts of certain disintegrants can swellto form matrices that may modulate the release of the drug substance.Accordingly, particularly when rapid release is required after the lagtime it is preferred that the disintegrants is employed in amounts of upto 10% by weight, e.g. about 5 to 10% by weight.

The core may additionally comprise common tablet excipients such asthose described above in relation to the coating material. Suitableexcipients include lubricants, diluents and fillers, including but notlimited to lactose (for example the mono-hydrate), ferric oxide,magnesium stearates and colloidal silica.

Lactose monohydrate is a disaccharide consisting of one glucose and onegalactose moiety. It may act as a filler or diluent in the tablets ofthe present invention. It may be present in a range of about 10 to 90%,preferably from 20 to 80%, and certain preferred embodiments from 65 to70%.

As stated above, it is an important aspect of the present invention thatcore is correctly located within the coating to ensure that a tablet hasthe appropriate coating thickness. In this way, lag times will bereliable and reproducible, and intra-subject and inter-subject variancein bioavailability can be avoided. It is advantageous to have a robustin process control to ensure that tablets in a batch contain coreshaving the appropriate geometry in relation to the coating. Controls canbe laborious in that they require an operator to remove random samplesfrom a batch and to cut them open to physically inspect the quality ofthe core (i.e. whether it is intact, and whether it is correctlylocated). Furthermore, if a significant number of tablets from thesample fail, a complete batch of tablets may be wasted. Applicant hasfound that if one adds to the core a strong colourant such as ironoxide, such that the core visibly contrasts with the coating when asstrong light is shone on the tablet, it is possible for any faults inthe position or integrity of the core to be picked up automatically by acamera appropriately located adjacent a tabletting machine to inspecttablets as they are ejected therefrom. In this way, if a faulty tabletis identified it is possible to halt production and correct any problemsin the manufacturing process quickly, thereby potentially avoidingwastage of batch quantities of tablets.

Whereas colourants contained in the core are useful for this purpose,equivalent solutions are also possible. For example, instead of acolourant, one can include a material that is opaque to x-rays, such asbarium sulphate. If an x-ray imager is then coupled to a tablet machine,the core will contrast with the coating material and the x-ray imagerwill pick up any faults in the positioning or integrity of the core in asimilar fashion.

The amount of drug substance employed in tablets of the presentinvention will depend on the particular drug substance used, thecondition of the patient and the nature and severity of the condition tobe treated. A typical drug loading might be from 1 to 50% by weight ofthe core.

As stated above a wide variety of drug substances may be employed in thepresent invention. Drugs for treating conditions the symptoms of whichresult from nocturnal circadian rhythms are particularly suitable.Accordingly, drugs for treating incontinence, sleep disorders, apnoea,asthma, epilepsy, bronchitis, parkinsonism, rheumatoid arthritis,allergic rhinitis and ischaemic heart diseases, cluster and migraineheadache, congestive heart failure, and depression are particularlysuitable for use in tablets according to the present invention. Further,drug substances that are metabolized by cytochrome P450 are alsoparticularly suitable, they include:—

Amitriptyline, caffeine, clomipramine, clozapine, fluvoxamine,haloperidol, imipramine, mexilitine, oestradiol, olanzepine,paracetamol, propranolol, tacrine, theophylline, warfarin, Bupropion,Cyclophosphamide, Celecoxib, Diclofenac, Flubiprofen, Ibuprofen,glimepirideindome, thacin, naproxen, phenyloin, piroxicam, tenoxicam,citalopram, diazepam, lansoprazole, omeprazole, pantoprozole,propanolol, topiramate, Aipranolol, chlorpromazine, clomipramine,codeine, Desipramine, dextromethorphan, diphenhydramine, donepezil,flecamide, fluoxetine, labetalol, Methadone, metoprolol, mianserin,nortripyline, ondansetron, oxprenolol, oxycodone, paroxetine,perhehexylene, pethidine, promethazine, risperdone, thioridazine,ticlopidine, timolol, trimipramine, venlafaxine, paracetamol,alprazolam, amiodarone, budesonide, buprenorphine, buspirone, CalciumChannel Blockers, carbamazepine, cisapride, clarithromycin, clonazepam,cocaine, cortisol, cyclosporine, dexamethasone, erythromycin, fentanyl,ketoconazole, losartan, miconazole, midazolam, quinidine, sertraline,statins, tacrolimus, tamoxifen, TCAs, triamzolam, zolpidem, or mixturesthereof.

Additional examples of drug classes and drugs that can be employed intablets of the present invention include:

antihistamines (e.g., azatadine maleate, brompheniramine maleate,carbinoxamine maleate, chlorpheniramine maleate, dexchlorpheniraminemaleate, diphenhydramine hydrochloride, doxylamine succinate,methdilazine hydrochloride, promethazine, trimeprazine tartrate,tripelennamine citrate, tripelennamine hydrochloride and triprolidinehydrochloride);antibiotics (e.g., penicillin V potassium, cloxacillin sodium,dicloxacillin sodium, nafcillin sodium, oxacillin sodium, carbenicillinindanyl sodium, oxytetracycline hydrochloride, tetracyclinehydrochloride, clindamycin phosphate, clindamycin hydrochloride,clindamycin palmitate HCL, lincomycin HCL, novobiocin sodium,nitrofurantoin sodium, metronidazole hydrochloride); antituberculosisagents (e.g., isoniazid);cholinergic agents (e.g., ambenonium chloride, bethanecol chloride,neostigmine bromide, pyridostigmine bromide);antimuscarinics (e.g., anisotropine methylbromide, clidinium bromide,dicyclomine hydrochloride, glycopyrrolate, hexocyclium methylsulfate,homatropine methylbromide, hyoscyamine sulfate, methantheline bromide,hyoscine hydrobromide, oxyphenonium bromide, propantheline bromide,tridihexethyl chloride);sympathomimetics (e.g., bitolterol mesylate, ephedrine, ephedrinehydrochloride, ephedrine sulphate, orciprenaline sulphate,phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride,ritodrine hydrochloride, salbutamol sulphate, terbutaline sulphate);sympatholytic agents (e.g., phenoxybenzamine hydrochloride);miscellaneous autonomic drugs (e.g., nicotine);iron preparations (e.g., ferrous gluconate, ferrous sulphate);haemostatics (e.g., aminocaproic acid);cardiac drugs (e.g., acebutolol hydrochloride, disopyramide phosphate,flecamide acetate, procainamide hydrochloride, propranololhydrochloride, quinidine gluconate, timolol maleate, tocainidehydrochloride, verapamil hydrochloride);antihypertensive agents (e.g., captopril, clonidine hydrochloride,hydralazine hydrochloride, mecamylamine hydrochloride, metoprololtartrate); vasodilators (e.g., papaverine hydrochloride);non-steroidal anti-inflammatory agents (e.g., choline salicylate,ibuprofen, ketoprofen, magnesium salicylate, meclofenamate sodium,naproxen sodium, tolmetin sodium);opiate agonists (e.g., codeine hydrochloride, codeine phosphate, codeinesulphate, dextromoramide tartrate, hydrocodone bitartrate, hydromorphonehydrochloride, pethidine hydrochloride, methadone hydrochloride,morphine sulphate, morphine acetate, morphine lactate, morphinemeconate, morphine nitrate, morphine monobasic phosphate, morphinetartrate, morphine valerate, morphine hydrobromide, morphinehydrochloride, propoxyphene hydrochloride);anticonvulsants (e.g., phenobarbital sodium, phenyloin sodium,troxidone, ethosuximide, valproate sodium);tranquilizers (e.g., acetophenazine maleate, chlorpromazinehydrochloride, fluphenazine hydrochloride, prochlorperazine edisylate,promethazine hydrochloride, thioridazine hydrochloride,trifluoroperazine hydrochloride, lithium citrate, molindonehydrochloride, thiothixine hydrochloride);chemotherapeutic agents (e.g., doxorubicin, cisplatin, floxuridine,methotrexate, combinations thereof);lipid lowering agents (e.g., gemfibrozil, clofibrate, HMG-CoA reductaseinhibitors, such as for example, atorvastatin, cerivastatin,fluvastatin, lovastatin, pravastatin, simvastatin);H.sub.2-antagonists (e.g., cimetidine, famotidine, nizatidine,ranitidine HCl);anti-coagulant and anti-platelet agents (e.g., warfarin, cipyridamole,ticlopidine);bronchodilators (e.g., albuterol, isoproterenol, metaproterenol,terbutaline);stimulants (e.g., benzamphetamine hydrochloride, dextroamphetaminesulphate, dextroamphetamine phosphate, diethylpropion hydrochloride,fenfluramine hydrochloride, methamphetamine hydrochloride,methylphenidate hydrochloride, phendimetrazine tartrate, phenmetrazinehydrochloride, caffeine citrate);barbiturates (e.g., amylobarbital sodium, butabarbital sodium,secobarbital sodium);sedatives (e.g., hydroxyzine hydrochloride, methprylon); expectorants(e.g., potassium iodide);antiemetics (e.g., benzaquinamide hydrochloride, metoclopropamidehydrochloride, trimethobenzamide hydrochloride);gastro-intestinal drugs (e.g., ranitidine hydrochloride); heavy metalantagonists (e.g., penicillamine, penicillamine hydrochloride);antithyroid agents (e.g., methimazole);genitourinary smooth muscle relaxants (e.g., flavoxate hydrochloride,oxybutynin hydrochloride);vitamins (e.g., thiamine hydrochloride, ascorbic acid);unclassified agents (e.g., amantadine hydrochloride, colchicine,etidronate disodium, leucovorin calcium, methylene blue, potassiumchloride, pralidoxime chloride.steroids, particularly glucocorticoids (e.g., prednisolone,methylprednisolone, prednisone, cortisone, hydrocortisone,methylprednisolone, betamethasone, dexamethasone, triamcinolone).

Notwithstanding the general applicability of the tablets in relation toa wide range of drug substances, the present invention is particularlysuited to delivery of the glucocorticosteroids aforementioned, andparticularly prednisone, prednisolone and methylprednisolone. Thesesteroids are useful in the treatment La, of rheumatoid arthritis andjoint pain. As already stated, the symptoms of these conditions appearaccording to a circadian rhythm and with great predictability during theearly hours of the morning. Accordingly, the glucocorticosteroids, andin particular prednisone are eminently suited for delivery from tabletsaccording to this invention not only because of their narrow absorptionwindow, but also because a tablet may be administered in the eveningbefore bedtime anytime around 8 pm until midnight, e.g. around 10-12 atnight, to deliver maximum plasma concentration of the drug substancebefore maximum secretion of JL-6 (which occur around 2 am to 4 am),thereby effectively addressing the underlying causes of the morningsymptoms. In this way, these symptoms are more effectively treated.

As used above, prednisone refers to the compound and its salts orderivatives thereof, including prednisone 21 acetate.

As used above, prednisolone refers to the compound and its salts orderivatives including the 21-acetate, its 21-tert-butyl acetate,21-succinate sodium salt, 21-stearoylglycolate, 21-m-sulphobenzoatesodium salt, and its trimethylacetate.

Methylprednisolone, as used above refers to the compound or and itssalts and derivatives thereof including its 21 acetate, 21-phosphatedisodium salt, 21-succinate sodium salt, and its acetonate.

Typically a core may contain about 0.1 to 50% by weight, moreparticularly 1 to 20%, still more particularly 1 to 10% by weight ofsteroid based on the total weight of the core. In the case ofprednisone, it may be employed in amounts to provide a total weight perunit dosage form of 1 or 5 mg, to offer convenience and flexibility ofdosing, although dosage forms containing larger or smaller amounts ofdrug substance could be employed if desired.

Particularly preferred tablets according to the invention comprising inthe core a glucocorticosteroid selected from the group consisting ofprednisone, prednisolone and methylprednislone, and cross-linkedpolyvinyl pyrollidone, cross-linked sodium carboxymethyl cellulose, andone or more adjuvants diluents, lubricants or filler materials ashereinabove described. Preferably the coating comprises a calciumphosphate salt, glyceryl behenate, cross-linked polyvinyl pyrollidoneand one or more adjuvants, diluents, lubricants or filler materials ashereinabove described.

The composition of one particularly preferred embodiment of theinvention is:

Core of 5 mg Prednisone Tablet: Prednisone 8.33%

Lactose monohydrate 64.47%

Povidone 6.67%

Croscarmellose sodium 18.33%Red ferric oxide 0.5%Magnesium stearate Vegetable origin 1.0%Colloidal silicon dioxide 0.5%

Coating

Dibasic calcium phosphate dihydrate 50%Glyceryl behenate 40%

Povidone 8.40%

Yellow ferric oxide 0.1%Magnesium stearate Vegetable origin 1.0%Colloidal silicon dioxide 0.5%

Another preferred embodiment is as follows:

Core of 1 mg Prednisone Tablet: Prednisone 1.67%

Lactose monohydrate 71.13%

Povidone 6.67%

Croscarmellose sodium 18.33%Red ferric oxide 0.5%Magnesium stearate Vegetable origin 1.0%Colloidal silicon dioxide 0.5%

Coating

Dibasic calcium phosphate dihydrate 50%Glyceryl behenate 40%

Povidone 8.40%

Yellow ferric oxide 0.1%Magnesium stearate Vegetable origin 1.0%Colloidal silicon dioxide 0.5%

It is surprising that the tablets containing the glucocorticosteroidsdisplay such rapid release given that the rate of release relies to someextent on the wetting of the core, and these steroids are ratherhydrophobic in nature.

The tablets described above are press-coated tablets comprising a coreand a coating covering said core. However, variants of this basicconstruction are within the ambit of the present invention. Thus, thepress-coating may be further coated with an outer coating that may befunctional and/or aesthetic in its design. For example, functionalcoatings may include the addition an immediate release coatingcontaining a drug substances that may be the same or different to thedrug substance contained in the core.

In this manner, the tablet can affect a pulsatile release that is of usein treating symptoms based on circadian rhythms, such as sleepdisorders. In this regard one can employ sedative hypnotics in suchdosage forms, for example those drug substances mentioned described inU.S. Pat. No. 6,485,746. Pulsatile release dosage forms may also findgeneral applicability with a wide range of active substances for thetreatment of a wide range of indications to provide patients with a moreconvenient dosage schedule. For example, pulsatile release can providean alternative to multiple administrations of immediate release forms.

Functional coatings also include enteric coatings covering thepress-coating. Enteric coated forms may be of use in treating localconditions in the bowel such as Crohn's disease, ulcerative colitis, IBSand IBD. In this embodiment, the enteric coating would prevent releaseof any drug before the tablet enters the bowel.

Aesthetic coatings include taste masking coatings and coloured coatingsas a generally well known in the art.

It is well known in the art that food can change the bioavailability ofa drug. Food can alter the bioavailability of a drug by various meanssuch as delaying gastric emptying, changes in gastrointestinal pH,changes in luminal metabolism, and physical and chemical reactions offood items with a dosage form or drug substance. This change inbioavailability as a consequence of food intake is often referred to asa “food effect”. Food effects are quite common in modified-releasedosage forms, and also for drugs that have either poor solubility orpoor permeability or both (BCS Class II, III, and IV).

The applicant has surprisingly found that a tablet that is adapted torelease all, or substantially all, of a drug contained therein within atime (T_(lag)) of between 2 and 6 hours (median time) afteradministration.

Furthermore, the applicant has surprisingly developed a tablet adaptedto release a drug substance after a lag time that can deliver a drug toa patient, which upon absorption the peak drug concentration C_(max)will be reached in a time T_(max) that is independent of a patient'sfood intake.

T_(max) is a term well known in the art that refers to the time elapsedbetween drug administration and the maximum plasma concentration C_(max)is reached. C_(max) is also an art recognized term that relates to thepeak plasma concentration of a drug.

T_(max) is an important parameter particularly in relation tomedicaments that are intended to be taken at a time convenient for apatient, but which release drug substances after a lag time in order tosynchronise drug release with a circadian rhythm, and in particular anocturnal circadian rhythm. By way of example, the glucocorticosteroids,referred to above, e.g. prednisone, are useful in the treatment of i.a.arthritic conditions such as rheumatoid arthritis and osteoarthritis.Debilitating symptoms are often experienced by a patient upon waking.Current therapy requires a patient to take Decortin® upon waking.However, this is not the most efficacious way of treating the symptoms,as they are believed to be associated with the secretion of IL-6, whichoccurs during the early morning hours, e.g. from about 2 to 4 am. Amedicament that can reach C_(max) that is coincident with or anticipatesthe release of IL-6 is potentially of greater benefit to a patient.Furthermore, given the varied lifestyles of individuals, patients takingmedicament between 8 pm and bedtime, e.g. from 10 pm to midnight, may bein a variety of fed states, it is even more advantageous that T_(max)should be independent of food intake.

Medicaments that can have a pre-determined lag time, and which releasedrug substance after this lag time in a manner that provides a T_(max)independent of considerations of the fed or fasted state of a patientare of potentially great benefit, not only in relation to theglucocorticosteroids and the treatment of arthritis, but for otheractive substances that are advantageously delivered in synchronicitywith a circadian rhythm, or even in relation to drug substances whoseefficacy depends on their ability to be delivered accurately to aparticular absorption site, or a locally diseased site along the GItract and bowel. Such medicaments are provided by the present invention.

Currently, there are no bioavailability or bioequivalence regulatoryguidelines available for T_(max) However, the Guidance For Industry“Food Effect Bioavailability and Fed Bioequivalence Studies”, USDepartment of Health (CDER) December 2002 suggests that any differencein T_(max) should not be clinically relevant. Whether such a differencewill be clinically relevant will depend on the drug delivered and theparticular indication. Applicant has found that in respect offormulations of the present invention the effect of food on the medianvalue of T_(max) is a difference of only about +/−20%, more particularly+/−10%

Still further, applicant has found medicaments containing drugsubstances exhibiting no significant effect of food with respect tobioavailability of the drug substance in terms of C_(max) and AUC.

The “food effect” as it relates to the bioavailability of drugsubstances is a well documented phenomenon in relation to drug deliverythat describes the variance in uptake of a drug substance by patientsdepending upon whether the patients are in fed or fasted states. Thepresence or absence of a food effect may be quantified by making Areaunder the Curve (AUC) and/or C_(max) measurements according to methodswell known in the art. Typically AUC measurements and C_(max)measurements are made by taking timed biological fluid samples andplotting the serum concentration of drug substance against time. Thevalues obtained represent a number of values taken from subjects acrossa patient population and are therefore expressed as mean valuesexpressed over the entire patient population. By comparing the mean AUCand/or C_(max) values, one can determine whether a drug substanceexperiences a food effect.

Food effect studies may be conveniently carried out on an adequatenumber of healthy volunteers, the number being sufficient to generatesufficient data for appropriate statistical assessment to be made.Preferably the number of subjects should not be less than 12.

To study the effect of food on the bioavailability of a drug substanceone may use any conventional study design known in the art, for examplea randomised; balanced single-dose, two-treatment, two-period,two-sequence crossover design. Analysis may be carried out using any ofthe programs known in the art such as SAS PROC GLM, software from theSAS institute, Cary N.C.

In quantitative terms, a drug substance may be said to exhibit no foodeffect if a 90% confidence interval (CI) for the ratio of means(population geometric means based on log transformed data) of fed andfasted treatments fall within the interval of 0.8 to 1.25 for AUC and/or0.7 to 1.43 for C_(max).

Accordingly, the present invention provides in another of its aspects atablet as defined herein above displaying a ratio AUC fed/fasted aftersingle dosing of 0.8 to 1.25 or the ratio C_(max) fed/fasted aftersingle dosing of 0.7 to 1.43.

A “fed” subject conveniently may be considered as a subject that hasfasted for at least 10 hours before receiving a standard FDA recognisedhigh fat meal. The medicament may then be administered with watershortly after completion of the meal, e.g. within 5 minutes thereof.Preferably no food should be taken for a period of, e.g. 4 hours afterreceiving medicament although small quantities of water may be permittedafter, e.g. 2 hours after receiving the medicament.

A “fasted” subject conveniently may receive medicament with water afterat least 10 hours fasting. Thereafter, no food may be taken for a periodof, e.g. 4 hours although small quantities of water may be taken after,e.g. 2 hours after receiving medicament.

A standard FDA high fat meal as referred to hereinabove may comprise anymeal that would be expected to provide maximal perturbation due to thepresence of food in the GI tract. Said high fat meal typically maycomprise 50% of its caloric value in fat. A representative example maybe 2 eggs fried in butter, 2 strips of bacon, 2 slices toast withbutter, 4 ounces fried potato, and 8 ounces milk.

By application of the teachings of the present invention tablets may beprovided that display reduced variability in resumption/bioavailabilitylevels achieved both for individual patients receiving a drug as well asbetween individuals.

The tablets of the present invention may be packaged in a variety ofways. Generally an article for distribution includes a container forholding the tablets. Suitable containers are well known to personsskilled in the art and include materials such as bottles, foil packs andthe like. In addition, the container will have a label and an insertthat describes the contents of the container and any appropriatewarnings or instructions for use. It is an advantage of the presentinvention that the insert and/or label may contain instructions that thetablet may be taken with or without food, or may be absent a warning orinstruction that the tablet should be taken only with food or onlywithout food.

The invention provides in another aspect, a method of forming tablets asherein above described. The tablets may be formed on conventional presscoating equipment. Typically such equipment is composed of a series ofdie are arranged on a rotating platform. The die are removably mountedin the platform such that differently sized die may be employed asappropriate. Each die is hollow to receive a lower punch. The punch ispositioned within the die such that the upper surface of the punch andthe inner surface of the die define a volume for receiving a preciseamount coating material. Once loaded, the platform is rotated until thedie is positioned under an upper punch. The upper punch is then urgeddown onto the coating material under a defined compression force and thecoating material is pre-compressed or tamped between the upper and lowerpunch. A pre-formed core is then fed into die to rest on the tampedcoating. Conventional press coating apparatus may be equipped withcentering devices that enable cores to be positioned both vertically andradially. This might be achieved by a tamping process, whereby aninitial amount of coating material is placed in a die and is tamped witha shaped punch, such as a pin punch, that leaves an indentation in thecoating material in which to receive a core. Thereafter, in a secondfilling operation, a precise amount of coating material is fed into thedie to cover the core, and an upper punch compresses the coatingmaterial with a defined compaction force to form tablets according tothe present invention.

The compression force applied during the tamping process is relativelylight and is just sufficient to provide a bed of coating material toreceive the core and to prevent movement of the coating material as aresult of centrifugal force. Subsequent compression to form the tabletmay be adjusted to give tablets of requisite hardness. Preferably, thiscompression force is 400 kg, although this may be adjusted by +/−30% inorder to give tablets of the required hardness.

The amount of coating material fed into the die can be precisely definedhaving regard to the density of the coating material to ensure aftercompression that the tablet is formed with the required coatingthickness about the (A-B) axis; and the dimensions of the die isselected to provide the thickness about the X-Y axis. Should it benecessary to change the thickness of the coating, die of appropriateinternal dimensions may be placed in the rotating platform, and theamount of coating material fed into the die may be adjusted accordingly.

Suitable rotary tablet machines having high process speeds are known inthe art and need no further discussion here.

Cores may likewise be formed using a conventional rotary tablet machine.Cores are preferably compressed under compression forces sufficient toprovide cores having a hardness of about 60 Newtons at least, e.g. 50 to70 Newtons. Cores having hardness in this range give desired releasecharacteristics. If desired, the cores can be formed at the same time asthe press coated tablets are produced. In such case, one might employ aManesty Dry Cota. Such a press consists of two side-by-side andinter-connected presses where the core is made on one press before beingmechanically transferred to the other press for compression coating.Such equipment and techniques for making tablets using such equipmentare known in the art and no more needs to be said about this here.

Cores are preferably formed according to wet granulation techniquesgenerally known in the art. In a typical procedure, core materials aresieved and blended. Granulating fluid, typically water is then added tothe blend and the mixture is homogenized to form a granulate, which isthen sprayed dried or dried on a fluid bed drier to obtain a granulatewith requisite residual moisture. Preferably the residual moisturecontent is from about 0.4 to 2.0% by weight. The granulate is then sizedby passing it through screens of desired aperture. At this stage, anyadjuvants are sized and added to the granulate to form the corecomposition suitable for compression. The skilled person will appreciatethat a coating composition can be formed in an analogous manner. Theskilled person will also appreciate that granulates may be obtainedhaving a range of particle sizes. It is preferred that the coatinggranulate has a fine fraction that is less than 30%. By “fine fraction”is meant granulate having particle size of up to about 63 microns.

Preferred features for the second and subsequent aspects of theinvention may be as for the first aspect mutatis mutandis.

FIG. 1: is a representation of a tablet in cross section showing thecoating and core and the axes (A-B) and (X-Y).

FIG. 2: Shows an in-vitro dissolution profile of the dosage form ofExample 2.

There now follows a series of examples that serve to illustrate theinvention.

EXAMPLE 1 Preparation of a Prednisone-Containing Tablet

The active core was prepared for the press coated system as follows. Thecomposition of the core is detailed in Table 1. Lactose monohydrate(Lactose Pulvis.H₂O®, Danone, France and Lactose Fast Flo® NF 316,Foremost Ing. Group, USA) is a filling agent with interesting technicaland functional properties. Lactose Pulvis.H₂O is used in a blendprepared by wet granulation and Lactose Fast Flo is used in a blendprepared for direct compression. Microcrystalline cellulose (Avicel® pH101, FMC International, Ireland) is used as an insoluble diluent fordirect compression. Polyvinyl pyrrolidone (Plasdone® K29-32, ISPTechnology, USA) is a granulating agent, soluble in water, which has theability of binding the powder particles. Croscarmellose sodium(Ac-Di-Sol®, FMC Corporation, USA) is used in the formulation as a superdisintegrant. As the external phase, magnesium stearate (Merck,Switzerland) was added as a lubricant and silicon dioxide (Aerosil® 200,Degussa AG, Germany) in order to improve flow properties of the granularpowder.

TABLE 1 Ingredients Content (mg/tablet) Prednisone 5.00 Lactose (LactosePulvis H₂O NF 316) 39.10 Polyvinyl pyrrolidone (Plasdone ® K29-32) 4.00Sodium carboxymethyl cellulose (Ac-Di-Sol ®) 11.00 Magnesium stearate0.60 Silicon dioxide (Aerosil ® 200) 0.30 Total 60.00

The coating of the prednisone press coated tablet is of a hydrophobic,water insoluble nature. This barrier is mainly composed of dibasiccalcium phosphate (Emcompress®, Mendell, USA) and glyceryl behenate(Compritol® 888ATO, Gattefossé, France). Polyvinylpyrrolidone (Plasdone®K29-32) is a granulating agent, soluble in water, which has the abilityof binding the powder particles. Yellow ferric oxide (Sicovit® Yellow10, BASF, Germany) was added as a dye. A detailed composition of thisbarrier blend is given in table 2.

TABLE 2 Composition of the coating Ingredients Content (%) Dibasiccalcium phosphate (Emcompress ®) 50.00 Glyceryl Behenate (Compritol ®888 ATO) 40.00 Polyvinylpyrrolidone (Plasdone ® K29-32) 8.40 YellowFerric Oxide (Sicovit ® yellow 10 E 172) 0.10 Silicon dioxide (Aerosil ®200) 0.50 Magnesium stearate 1.00 Total 100.00

The required amounts of prednisone, Ac-Di-Sol®, Lactose Pulvis H₂O®,Plasdone® K29-32 were weighed and manually sieved with a screen having0.710 mm apertures. The components were homogeneously mixed in aNiro-Fielder PMA 25-litre mixing granulator for 6 min at impeller speed250 rpm without chopper. A prednisone assay was performed on thispremix. Subsequently, the granulating solution (purified water, 25.47%of the weight of the dry blend) was added within 4 min at impeller speed250 rpm and chopper speed 1500 rpm, using a nozzle H1/4VV-95015(spraying rate of 250 g/min). Mixing was continued for homogenisationand massing of the wet mass for 3 min at impeller speed 500 rpm andchopper speed 3000 rpm.

The mixed wet granulate was then dried in a Glatt WSG5 fluidised air beddrier. The inlet temperature was maintained at 45° C. during drying. Thedrying lasted 20 min to get a granulate with a residual moisture lessthan 2.5%. The yielded dry granulate was calibrated in a Frewitt MGI 205granulator using a screen with 0.8 mm apertures for 3 min at speed 244osc/min (graduation 7). Appropriate amounts of Aerosil® 200 andmagnesium stearate were manually sieved using a screen, with 1.0 mmapertures. Half of the dry granulate was put in a Niro-Fielder PMA25-litre mixing granulator, followed by Aerosil® 200 and then by theother half of the dry granulate. The ingredients were mixed for 2 min atimpeller speed 250 rpm. Finally, magnesium stearate was added and mixingwas continued for 2 min at impeller speed 250 rpm.

The coating blend was prepared according to the process described below.Batch size for the bather blend was 13 kg. Weighed amounts ofEmcompress®, Compritol® 888 ATO, Lactose pulvis.H2O®, Plasdone® K29-32and Sicovit® Yellow 10 E 172 were manually sieved with a screen having0.710 mm apertures. They were placed in a Niro-Fielder PMA 65-litremixing granulator. Then, the components were homogeneously mixed for 6min, at impeller speed 200 rpm, without chopper. Subsequently, thegranulating solution (purified water, 8.12% of the weight of the dryblend) was added within 2 min at impeller speed 200 rpm and chopperspeed 1500 rpm using a nozzle 4.9 (spraying rate of 520 g/min). Mixingwas continued for homogenisation and massing for 1 min at impeller speed400 rpm and chopper speed 3000 rpm.

The mixed wet granulate was then dried in a Niro-Fielder TSG 2 fluidisedair bed dryer. The inlet temperature was maintained at 45° C. duringdrying. The drying lasted 33 min to have residual moisture less than2.5%. The yielded dry granulate was calibrated in a Frewitt MGI 205granulator using a screen having 0.8 mm apertures for 4 min at speed 244osc/min (graduation 7). Appropriate amounts of Aerosil® 200 andmagnesium stearate were manually sieved using a screen with 1.0 mmapertures.

Half of the dry granulate was put in a Niro-Fielder PMA 65-litre,followed by Aerosil® 200 and then by the other half of the drygranulate. The ingredients were mixed for 2 min at impeller speed 200rpm, without chopper. Finally, magnesium stearate was added and mixingwas continued for 2 more minutes at impeller speed 200 rpm, withoutchopper.

440 mg of coating blend was press coated on a core to provide presscoated tablets (9 mm diameter). 305 mg of coating blend was press coatedon a core to provide press coated tablets (8 mm diameter). Thesedifferent press coatings were done utilising a Kilian RUD tablettingmachine. First and second loading hoppers are filled up with the coatinggranulate. Between the two loading hoppers, the machine is equipped witha transfer system adapted to feed the cores. For each tablet, the firstloading hopper supplies with about half of the quantity to be applied tothe core. Then, the feeding system provides and positions a core centredin the die. Subsequently, the second loading hopper supplies with theother half of the quantity to be applied to the core. The compressionstep then occurs.

TABLE 3 Equipment implemented for the manufacturing process EquipmentBrand name/Type Manufacturer/Supplier Mixing granulator Niro-Fielder PMAAéromatic-Fielder AG, 25/65 litres Bubendorf, Switzerland Fluidised airbed Glatt WSG5 Maschinen und apparatebau AG, dryer Pratteln, SwitzerlandFluidised air bed Niro-Fielder TSG 2 Aéromatic-Fielder AG, dryerBubendorf, Switzerland Granulator Frewitt MGI 205 Frewitt SA,Granges-Pacot, Switzerland Infrared moisture Mettler PE 360 MettlerToledo AG, Greifensee, analyser Moisture Analyzer Switzerland Multilayertablet Hata HT-AP55LS- Elisabeth-Carbide, Antwerp, press U/3L BelgiumDry coating tablet Kilian RUD Kilian & Co GmbH, Cologne, press Germany

EXAMPLE 2 In Vitro Dissolution Profile

The in vitro dissolution profile of a tablet containing a 5 mg loadingof prednisone prepared according to the method of Example 1 wasdetermined using USP dissolution apparatus No. 2 (paddles) andstationary baskets and applying a stirring rate of 100 rpm. Thedissolution medium was purified water, with a volume of 500 ml.

After 4 hours no drug substance release is observed. However, within 4.5hours there is approximately 80% release and by 5 hours 100% release ofthe drug substance (see FIG. 2).

EXAMPLE 3

A study was carried out to determine the effect of food on thebioavailability of a 5 mg prednisone tablet described above.

The study did not compare the tablet in the fed and fasted state.Rather, the study was adjusted to take into account thechrono-pharmacokinetics of prednisone and the fact that it is to beadministered in the evening, e.g. about 8 pm, which is required in orderthat the blood plasma levels will peak before secretion of IL-6 toimprove the efficacy of the treatment. Thus the study was designed tocompare the tablet during real time administration and with likely foodintake scenarios at this time. It was considered unreasonable that at 8pm a subject would be approximately 8 hours fasted. Accordingly, thefollowing food intake scenarios were tested:

a) To simulate a fasted state at 8 pm in the evening, a light meal wasgiven 2½ hours before administration that contained a limited number ofcalories (i.e. 22% of total daily calories and with a limited fatcontent of 15.5 g) and being devoid of any slowly digestible nutrients.This is called the “semi-fasted” state.The composition of this meal consisted of brown bread, margarine, cheesespread, an apple (skin removed) and fruit cocktail in syrup.b) Fed state is simulated by giving a higher fat meal ½ hour beforedosing containing 35% of the daily intake of calories and 26 g of fat.

An assumption made was that in the case of the semi-fasted state, after2½ hours the stomach was already emptied, or substantially emptied offood,

The composition of the high fat meal was pasta with spaghetti sauce,soup and vegetables, Apple juice, Ice cream and whipped cream.

The methodology consisted of an open, randomized, 3-period crossoversingle oral dose study with 7 days washout periods. The patientpopulation consisted of 27 healthy male volunteers.

The pharmacokinetics of the formulation was compared for each of the fedand semi-fasted states with a standard immediate release form(Decortin®) administered at 2 am.

In the semi-fasted state the formulation exhibited a median lag time of3.5 hours. Relative to Decortin® dosed at 2 am, the formulation wasfully bioequivalent with a C_(max) of 97% and relative bioavailabilityof 101% (AUC_(0-infinity)).

In the fed state, the median lag time was 4 hours. C_(max) was 105%compared to Decortin®, and relative bioavailability (AUC_(0-infinity))was 113%.

Compared to the formulation in the semi-fasted state, the formulation inthe fed state was 108% on C_(max) and 112% on AUC_(0-infinity)

These results demonstrate that formulations of the present inventiondisplay excellent bioavailability with no significant effect of food.

1. A dosage form comprising a core comprising a drug, and a coatingaround the core, wherein the drug comprises a glucocorticosteroid activesubstance selected from prednisone, prednisolone, or methylprednisolone,wherein the core further comprises at least one disintegrating agentthat effervesces and/or swells in the presence of aqueous media therebyproviding a force necessary to rupture the coating, wherein the coatingcomprises at least one insoluble or poorly water soluble hydrophobicmaterial such that the drug is released from the core as a result of therupturing of the coating and not as a result of drug diffusing throughthe coating, and wherein the coating ruptures upon immersion in anaqueous medium after a period of between about 2 to about 6 hours torelease the drug.
 2. The dosage form according to claim 1, wherein thecoating is a water insoluble or poorly soluble hydrophobic material. 3.The dosage form according to claim 1, wherein the coating comprises atleast one water insoluble or poorly soluble hydrophobic material chosenfrom hydrophobic cellulosic derivatives and polymers selected fromalkylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxymethyl cellulose and derivatives thereof; polymethacrylicpolymers, polyvinyl acetate polymers, cellulose acetate polymers; fattyacid esters, fatty acid salts; long chain fatty alcohols;polyoxyethylene alkyl ethers; polyoxyethylene stearates; sugar esters;lauroyl macrogol-32 glyceryl, stearoyl macrogol-32 glyceryl andcombinations thereof.
 4. The dosage form according to claim 1, whereinthe coating comprises calcium phosphate salt, glyceryl behenate,polyvinyl pyrollidone, or mixtures thereof.
 5. The dosage form accordingto claim 1, comprising cross-linked polyvinyl pyrollidone andcroscarmellose sodium.
 6. The dosage form according to claim 1comprising 1 mg prednisone.
 7. The dosage form according to claim 1,comprising 2 mg prednisone.
 8. The dosage form according to claim 1,comprising 5 mg prednisone.
 9. The dosage form according to claim 1,having an in vitro dissolution profile using USP dissolution apparatusNo. 2, at a stirring rate of 100 rpm and in a dissolution medium ofpurified water (500 ml) that comprises a median lag time of about 4hours with at least about 80% of a drug substance being released afterabout 4.5 hours and about 100% of the drug substance being releasedafter about 5 hours.
 10. The dosage form according to claim 1, that is atablet.
 11. A method of treating rheumatoid arthritis by providing to apatient in need of treatment a dosage form according to claim
 1. 12. Amethod of treating rheumatoid arthritis in a patient in need thereofcomprising administering to the patient a dosage form comprising aglucocorticosteroid active substance selected from prednisone,prednisolone, or methylprednisolone, wherein the dosage form releasesall, or substantially all, of the glucocorticosteroid active substancecontained therein within a time (T_(lag)) of between 2 and 6 hours(median time) after administration, wherein release of theglucocorticosteroid active substance from the dosage form does not occurby means of diffusion through the dosage form, and wherein the ratio ofmeans (population geometric means based on log transformed data) of fedand fasted treatments falls within the interval of 0.8 to 1.25 for areaunder the curve (AUC) and/or within the interval of 0.7 to 1.43 for peakplasma concentration (C_(max)), wherein fed treatment refers toadministration of the dosage form within 0.5 hours of a full meal andfasted treatment refers to administration of the dosage form with 2.5hours of no more than a light meal.
 13. The method according to claim12, wherein the dosage form releases all, or substantially all of a drugsubstance contained therein within about ½ hour to about 1 hour afterthe T_(lag).
 14. The method according to claim 12, wherein intra-subjector inter-subject variability in Tmax differs by less than +/−20% whetheror not a patient is in a fed or a fasted (fed/fasted) state.
 15. Themethod according to claim 12, wherein said dosage form has an in vitrodissolution profile using USP dissolution apparatus No. 2, at a stirringrate of 100 rpm and in a dissolution medium of purified water (500 ml)that comprises a median lag time of about 4 hours with at least about80% of the glucocorticosteroid active substance being released after 4.5hours and about 100% of the drug substance being released release after5 hours.
 16. The method according to claim 12, wherein the dosage formcomprises 1 mg prednisone.
 17. The method according to claim 12, whereinthe dosage form comprises 2 mg prednisone.
 18. The method according toclaim 12, wherein the dosage form comprises 5 mg prednisone.
 19. Themethod according to claim 12, wherein the dosage form is administered inthe evening between around 8 pm until bedtime.
 20. The method accordingto claim 12, wherein the dosage form is a tablet.